The objective of the proposed research is to define the mechanisms of impairments in T cells. Many of the sequelae of alcoholism such as increased infections and tumors and autoimmune diseases are likely to be due to impairments in the immune system. Work from this laboratory has shown that alcohol ingestion in a murine model results in marked changes in T-cell-dependent immune responses. These changes have been shown by us to be associated with increased susceptibility to bacterial and viral infections. The studies in the present proposal are designed to define the mechanisms of these noted changes in immunity. Emphasis will be placed on studies of T-cell function at the cellular level, and an important line of research will be the studies of intracellular events after stimulation of T-cells with mitogen (concanavalin (A), alloantigens (stimulation through the T-cell receptor), and monoclonal antibody to the T-cell receptor-associated CD3 complex. Studies are also proposed to study in detail changes in T-cell-dependent antibody production, again, with the purpose to define mechanisms of ethanol impairments. In the previous grant period it has been shown that ethanol impairs resistance to the facultative intracellular bacterium, Listeria monocytogenes, and a respiratory virus, Sendai. The present proposal will expand these studies, and a number of studies are proposed to explore mechanisms of these changes. Although a number of in vitro functional studies are proposed, we have developed in vivo assays to study both T-cell and B-cell responses. These experiments will provide data relevant to the effects of ethanol on these cells in their natural environment. It is also proposed that both acute and chronic ethanol feeding be studied. The studies proposed will provide a great deal of information on the mechanisms of ethanol-associated changes in T-cell-mediated immune systems.